Identification and Characterization of Neural Progenitor Cells in the Adult Mammalian Brain

109 Pages·2009·2.472 MB·English

by  Jose Manuel Garcia-Verdugo, Arturo Alvarez-Buylla, Sara Gil-Perotín (auth.)

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Prof. Dr. M. FROTSCHER, Institut für Anatomie und Zellbiologie, Abteilung für Neuroanatomie,
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Advances in Anatomy,
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Co-ordinating Editor
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J.-P. Timmermans, Antwerpen
Sara Gil-Perotín, Arturo Álvarez-Buylla
and José Manuel García-Verdugo
Identification
and Characterization
of Neural Progenitor
Cells in the Adult
Mammalian Brain
With 31 Figures
Sara Gil-Perotín Arturo Álvarez-Buylla
Instituto Cavanilles de Biodiversitat i Neurosurgery Research
Biologia Evolutiva 10 Kirkham St., Room K-127
Polígono La Coma s/n San Francisco, CA 94143
46980 Paterna (Valencia) USA
Spain e-mail: [email protected]
e-mail: [email protected]
José Manuel García-Verdugo
Centro de Investigación Príncipe Felipe
Avda. Autopista El Saler, 16,
46013 Valencia
Spain
Instituto Cavanilles de Biodiversitat i
Biologia Evolutiva
Polígono La Coma s/n
46980 Paterna (Valencia)
Spain
e-mail: [email protected]
ISSN 0301-5556
ISBN 978-3-540-88718-8 e-ISBN 978-3-540-88719-5
Library of Congress Control Number: 2008939433
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Acknowledgments
We are grateful to Vicente Hernández Rabaza, Clara Alfaro-Cervelló, and Melissa
Lezameta Morgan for providing us with some images, and to Francisco Clascá,
Mario Soriano-Navarro, and Maria Duran Moreno for their useful comments.
List of Contents
1 Historic Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Research Methodologies for Adult Neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1 Immunohistochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1.1 Markers of Proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1.2 Phenotypic Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2 Electron Microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.3 Neurosphere Assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.3.1 Limitations of the Neurosphere Assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.4 Fluorescence-Assisted Cell Sorting (FACS) Analysis
in Stem Cell Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.5 Transgenic Animals and the cre–lox System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.6 Transplantation of Adult NSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.7 Integration and Functionality of Newborn Cells in the Adult Brain . . . . . . . . 25
3 Neurogenesis in the Intact Adult Mammalian
Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1 Description of Neurogenic Regions in the Adult Mammalian Brain . . . . . . . 27
3.1.1 Subventricular Zone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1.2 Hippocampal Dentate Gyrus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.1.3 Concept of Neurogenic Niche . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.2 Identification of the Adult Neural Stem Cell in the SVZ . . . . . . . . . . . . . . . . . . 47
3.3 Other Proliferating and Neurogenic Centers in the Adult Brain . . . . . . . . . . . 49
3.3.1 The Subcallosal Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3.3.2 The Central Canal of the Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3.4 Distinct Features of Different Species: Comparative
Study of Mice and Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.4.1 Bovine Lateral Ventricles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.4.2 Rabbit Lateral Ventricles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
3.4.3 Primate Lateral Ventricles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
3.4.4 Human Lateral Ventricles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
4 Oncogenesis vs. Neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
5 Adult Neurogenesis Under Pathological Stimulation: Ischemia. . . . . . . . . . . . 67
5.1 Concept and Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
5.2 Effects of Ischemia on the Brain and the SVZ . . . . . . . . . . . . . . . . . . . . . . . . . . 69
viii List of Contents
5.3 Extracellular Factors and Neurogenesis After Stroke . . . . . . . . . . . . . . . . . . . . 73
5.4 Stem Cell-Based Therapies in Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6 Therapeutic Potential of Neural Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
7 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Abstract
Adult neurogenesis has been questioned for many years. In the early 1900s, a dogma
was established that denied new neuron formation in the adult brain. In the last
century, however, new discoveries have demonstrated the real existence of prolif-
eration in the adult brain, and in the last decade, these studies led to the identifica-
tion of neural stem cells in mammals. Adult neural stem cells are undifferentiated
cells that are present in the adult brain and are capable of dividing and differentiat-
ing into glia and new neurons. Newly formed neurons terminally differentiate into
mature neurons in the olfactory bulb and the dentate gyrus of the hippocampus.
Since then, a number of new research lines have emerged whose common objec-
tive is the phenotypical and molecular characterization of brain stem cells. As a
result, new therapies are successfully being applied to animal models for certain
neurodegenerative diseases or stroke. This work is being or will be extended to the
adult human brain, and so it provides purpose and hope to all previous studies in
this field. We are still far from clinical therapies because the mechanisms and func-
tions of these cells are not completely understood, but we appear to be moving in
the right direction.
Abbreviations
3HT Tritiated thymidine
AP Alkaline phosphatase
APB AraC plus procarbazol
AraC Cytosine-beta-D-arabinofuranoside
BDNF Brain-derived neurotrophic factor
bFGF Basic fi broblastic growth factor
BMSC Bone marrow stem cell
BrdU Bromodeoxyuridine
CC Corpus callosum
CSF Cerebrospinal fl uid
DAB Diaminobenzidine
Dcx Doublecortin
DG Dentate gyrus
EGF Epidermal growth factor
EM Electron microscopy
ENU N-ethyl-N-nitrosourea
EPO Erythropoietin
ESC Embryonic stem cell
FACS Fluorescence-assisted cell sorting
GCL Granular cell layer
GDNF Glial-derived neurotrophic factor
GFAP Glial fi brillary acidic protein
GFP Green fl uorescent protein
HB-EGF Heparin-binding epidermal growth factor
HH3 Phosphorylated histone H3
IGF-1 Insulin-like growth factor-1
LacZ Beta-galactosidase
LM Light microscopy
ML Molecular layer
MRI Magnetic resonance imaging
NSC Neural stem cell
OB Olfactory bulb
OPC Oligodendrocyte precursor cell
xii Abbreviations
OT Olfactory tract
PCNA Proliferating cell nuclear antigen
PDGF Platelet-derived growth factor
PSA-NCAM Polysialylated neural cell adhesion molecule
PTEN Phosphatase and tensin homolog deleted on chromosome 10
RER Rough endoplasmic reticulum
RMS Rostral migratory stream
SCR Subcallosal region
SEM Scanning electron microscopy
SGZ Subgranular zone
SVZ Subventricular zone
Tuj1 Beta-tubulin III
VEGF Vascular endothelial growth factor
VZ Ventricular zone